Enhanced DNA repair through droplet formation and p53 oscillations.

Living organisms are constantly exposed to DNA damage, and optimal repair is therefore crucial. A characteristic hallmark of the response is the formation of sub-compartments around the site of damage, known as foci. Following multiple DNA breaks, the transcription factor p53 exhibits oscillations in its nuclear concentration, but how this dynamics can affect the repair remains unknown. Here, we formulate a theory for foci formation through droplet condensation and discover how oscillations in p53, with its specific periodicity and amplitude, optimize the repair process by preventing Ostwald ripening and distributing protein material in space and time. Based on the theory predictions, we reveal experimentally that the oscillatory dynamics of p53 does enhance the repair efficiency. These results connect the dynamical signaling of p53 with the microscopic repair process and create a new paradigm for the interplay of complex dynamics and phase transitions in biology.

Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida.

The AIM2 inflammasome detects double-stranded DNA in the cytosol and induces caspase-1-dependent pyroptosis as well as release of the inflammatory cytokines interleukin 1ß (IL-1ß) and IL-18. AIM2 is critical for host defense against DNA viruses and bacteria that replicate in the cytosol, such as Francisella tularensis subspecies novicida (F. novicida). The activation of AIM2 by F. novicida requires bacteriolysis, yet whether this process is accidental or is a host-driven immunological mechanism has remained unclear. By screening nearly 500 interferon-stimulated genes (ISGs) through the use of small interfering RNA (siRNA), we identified guanylate-binding proteins GBP2 and GBP5 as key activators of AIM2 during infection with F. novicida. We confirmed their prominent role in vitro and in a mouse model of tularemia. Mechanistically, these two GBPs targeted cytosolic F. novicida and promoted bacteriolysis. Thus, in addition to their role in host defense against vacuolar pathogens, GBPs also facilitate the presentation of ligands by directly attacking cytosolic bacteria.

A model of d-wave superconductivity, antiferromagnetism, and charge order on the square lattice.

We describe the confining instabilities of a proposed quantum spin liquid underlying the pseudogap metal state of the hole-doped cuprates. The spin liquid can be described by a SU(2) gauge theory of Nf = 2 massless Dirac fermions carrying fundamental gauge charges-this is the low-energy theory of a mean-field state of fermionic spinons moving on the square lattice with π-flux per plaquette in the ℤ2 center of SU(2). This theory has an emergent SO(5)f global symmetry and is presumed to confine at low energies to the Néel state. At nonzero doping (or smaller Hubbard repulsion U at half-filling), we argue that confinement occurs via the Higgs condensation of bosonic chargons carrying fundamental SU(2) gauge charges also moving in π ℤ2-flux. At half-filling, the low-energy theory of the Higgs sector has Nb = 2 relativistic bosons with a possible emergent SO(5)b global symmetry describing rotations between a d-wave superconductor, period-2 charge stripes, and the time-reversal breaking "d-density wave" state. We propose a conformal SU(2) gauge theory with Nf = 2 fundamental fermions, Nb = 2 fundamental bosons, and a SO(5)f×SO(5)b global symmetry, which describes a deconfined quantum critical point between a confining state which breaks SO(5)f and a confining state which breaks SO(5)b. The pattern of symmetry breaking within both SO(5)s is determined by terms likely irrelevant at the critical point, which can be chosen to obtain a transition between Néel order and d-wave superconductivity. A similar theory applies at nonzero doping and large U, with longer-range couplings of the chargons leading to charge order with longer periods.

Enhanced Superconducting Diode Effect due to Coexisting Phases.

The superconducting diode effect refers to an asymmetry in the critical supercurrent J_{c}(n[over ^]) along opposite directions, J_{c}(n[over ^])≠J_{c}(-n[over ^]). While the basic symmetry requirements for this effect are known, it is, for junction-free systems, difficult to capture within current theoretical models the large current asymmetries J_{c}(n[over ^])/J_{c}(-n[over ^]) recently observed in experiment. We here propose and develop a theory for an enhancement mechanism of the diode effect arising from spontaneous symmetry breaking. We show-both within a phenomenological and a microscopic theory-that there is a coupling of the supercurrent and the underlying symmetry-breaking order parameter. This coupling can enhance the current asymmetry significantly. Our work might not only provide a possible explanation for recent experiments on trilayer graphene but also pave the way for future realizations of the superconducting diode effect with large current asymmetries.

Insight from Electrochemical Analysis in the Radical Cation State of a Monopyrrolotetrathiafulvalene Based [2]Rotaxane.

Mechanically interlocked molecules are a class of compounds used for controlling directional movement when barriers can be raised and lowered using external stimuli. Applied voltages can turn on redox states to alter electrostatic barriers but their use for directing motion requires knowledge of their impact on the kinetics. Herein, we make the first measurements on the movement of cyclobis(paraquat-p-phenylene) (CBPQT4+) across the radical-cation state of monopyrrolotetrathiafulvalene (MPTTF) in a [2]rotaxane using variable scan-rate electrochemistry. The [2]rotaxane is designed in a way that directs CBPQT4+ to a high-energy co-conformation upon oxidation of MPTTF to either the radical cation (MPTTF•+) or the dication (MPTTF2+). 1H NMR spectroscopic investigations carried out in acetonitrile at 298 K showed direct interconversion to the thermodynamically more stable ground-state co-conformation with CBPQT4+ moving across the oxidized MPTTF2+ electrostatic barrier. The electrochemical studies revealed that interconversion takes place by movement of CBPQT4+ across both the MPTTF•+ (19.3 kcal mol-1) and MPTTF2+ (18.7 kcal mol-1) barriers. The outcome of our studies shows that MPTTF has three accessible redox states that can be used to kinetically control the movement of the ring component in mechanically interlocked molecules.

Hydrazine Sulfonic Acid, NH3 NH(SO3 ), the Bigger Sibling of Sulfamic Acid.

The reaction of hydrazine hydrate, N2 H4 ⋅ H2 O, and SO3 leads to hydrazine sulfonic acid (Pca21 , a=849.59(4) pm, b=482.18(2) pm, c=832.17(4) pm). Structure elucidation reveals the zwitter-anionic nature of the compound according to NH3 NH(SO3 ). With the barium salt Ba[NH2 NH(SO3 )]2 (H2 O), a first salt of hydrazine sulfonic acid has been prepared (P 1 ‾ $\bar 1$ , a=489.75(5) pm, b=737.52(7) pm, c=1317.4(1) pm, α=88.238(4)°, ß=84.761(4)°, γ=79.701(4)°). The compounds were characterized by vibrational spectroscopy, DFT calculations and thermal analyses.

Triflate's bigger brother: The unprecedented tribrate anion, [Br3 CSO3 ].

The synthesis of the unprecedented [Br3 CSO3 ]- anion starts with the bromination of phenylmethanesulfonate, C6 H5 OSO2 CH3 , with KOBr leading to C6 H5 OSO2 CBr3 . The formation of the [CBr3 ] moiety has been proved, also by an X-ray structure determination of the compound (triclinic, P-1, a=685.9(2), b=698.1(2), c=1190.2(3) pm, α=93.99(1)°, ß=97.42(1)°, γ=94.45(1)°). The ester C6 H5 OSO2 CBr3 can be split under basic conditions. The resulting acid provides access to the yet unknown tribromomethanesulfates ("tribrates"). K[Br3 CSO3 ] ⋅ H2 O, the first tribrate known so far has been characterized comprehensively, including an X-ray structure determination (monoclinic, C2/c, a=2267.1(2), b=1282.25(8), c=2618.2(2) pm, ß=111.266(2)°), vibrational spectroscopy and theoretical calculations. Moreover, the thermal analysis shows that, after loss of the crystal water, the tribrate decomposes between 530 and 630 K.

The Divalent Lanthanoid Triflates Ln(CF3SO3)2(CH3CN) (Ln=Sm, Eu): Structure, Luminescence, and Magnetism.

The reaction of the trivalent lanthanoide triflates Ln(OTf)3 (Ln=Sm, Eu; OTf=CF3SO3 -) with the respective metals in acetonitrile leads to the Ln(II)-triflates Eu(OTf)2(CH3CN) (monoclinic, P21/n, Z=4, a=1053.54(1), b=610.28(5), c=1946.92(2) pm, ß =98.611(4)) and Sm(OTf)2(CH3CN) (monoclinic, P21/n, Z=4, a=1054.41(4), b=612.16(2), c=1952.65(7) pm, ß =98.524(2)). The isotypic strontium compound Sr(OTf)2(CH3CN) (monoclinic, P21/n, Z=4, a=1056.39(5), b=610.05(3), c=1950.1(1) pm, ß =98.900(2)°) has been obtained from SrCO3 and triflic acid. The compounds have been investigated by X-ray diffraction, vibrational spectroscopy, luminescence spectroscopy, cyclic voltammetry, thermal analysis, and magnetic measurements.

Stabilization of Pr4+ in Silicates─High-Pressure Synthesis of PrSi3O8 and Pr2Si7O18.

The reaction between PrO2 and SiO2 was investigated at various pressure points up to 29 GPa in a diamond anvil cell using laser heating and in situ single-crystal structure analysis. The pressure points at 5 and 10 GPa produced Pr2III(Si2O7), whereas Pr4IIISi3O12 and Pr2IV(O2)O3 were obtained at 15 GPa. Pr4IIISi3O12 can be interpreted as a high-pressure modification of the still unknown orthosilicate Pr4III(SiO4)3. PrIVSi3O8 and Pr2IVSi7O18 that contain praseodymium in its rare + IV oxidation state were identified at 29 GPa. After the pressure was released from the reaction chamber, the Pr(IV) silicates could be recovered, indicating that they are metastable at ambient pressure. Density functional theory calculations of the electronic structure corroborate the oxidation state of praseodymium in both PrIVSi3O8 and Pr2IVSi7O18. Both silicates are the first structurally characterized representatives of Pr4+-containing salts with oxoanions. All three silicates contain condensed networks of [SiO6] octahedra which is unprecedented in the rich chemistry of lanthanoid silicates.

Tunable Superconductivity and Möbius Fermi Surfaces in an Inversion-Symmetric Twisted van der Waals Heterostructure.

We theoretically study a moiré superlattice geometry consisting of mirror-symmetric twisted trilayer graphene surrounded by identical transition metal dichalcogenide layers. We show that this setup allows us to switch on or off and control the spin-orbit splitting of the Fermi surfaces via application of a perpendicular displacement field D_{0} and explore two manifestations of this control: first, we compute the evolution of superconducting pairing with D_{0}; this features a complex admixture of singlet and triplet pairing and, depending on the pairing state in the parent trilayer system, phase transitions between competing superconducting phases. Second, we reveal that, with application of D_{0}, the spin-orbit-induced spin textures exhibit vortices which lead to "Möbius fermi surfaces" in the interior of the Brillouin zone: diabatic electron trajectories, which are predicted to dominate quantum oscillation experiments, require encircling the Γ point twice, making their Möbius nature directly observable. Further, we show that the superconducting order parameter inherits the unconventional, Möbius spin textures. Our findings suggest that this system provides a promising experimental avenue for systematically studying the impact of spin-orbit coupling on the multitude of topological and correlated phases in near-magic-angle twisted trilayer graphene.

The Cyanido-Sulfate Anion [SO3 CN].

The reaction of the pyridine adduct of SO3 and tetra-n-butyl-ammonium cyanide, [N(n Bu)4 ][CN] at room temperature leads to the unprecedented cyanido-sulfate anion [SO3 CN]- stabilized in the salt [N(n Bu)4 ][SO3 CN]. The anion is a pseudo-halogen congener of the well-known fluoro- and chloro-sulfates. The new anion has been studied by vibrational spectroscopy and theoretical calculations.

Trichlates, an Unattended Class of Compounds: Characterization of Cl3 CSO2 Cl, and (H5 O2 )[Cl3 CSO3 ].

Chlorination of CS2 leads to trichloromethanesulfenyl chloride, Cl3 CSCl, in moderate yields. The oxidation of Cl3 CSCl with H2 O2 gives Cl3 CSO2 Cl, the chloride of trichloromethanesulfonic acid. Cl3 CSO2 Cl is the crucial product for the preparation of trichloromethanesulfonates ("trichlates") and has been characterized by IR spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction measurements (P-1, a=609.99(5) pm, b=727.45(6) pm, c=782.49(7) pm, α=80.644(3)°, ß=85.175(3)°, γ=88.311(3)°. The acid Cl3 CSO3 H can be gained in form of the hydrate (H5 O2 )[Cl3 CSO3 ] in two different modifications (I: monoclinic, P21 /n, Z=8, a=1292.47(7) pm, b=605.89(2) pm, c=2661.1(1) pm, ß=98.708(4)°, V=1672.8(1) Å3 ; II: monoclinic, Cc, Z=4, a=699.80(5) pm, b=1054.72(8) pm, c=1139.88(8) pm, ß=95.303(3)°, V=837.7(1) Å3 . Both modifications have been investigated by IR spectroscopy, thermal analyses and theoretical calculations.

Impact of 1,10-Phenanthroline-Induced Intermediate Valence on the Luminesence of Divalent Europium Halides.

Starting from EuX2 (X = Cl, Br, I), we systematically investigated a variety of divalent europium complexes containing bidentate 1,10-phenanthroline (Phen) ligands. Depending on the Eu/Phen ratio, mono-, di-, and polynuclear complexes are formed, with the latter yielding one-dimensional ∞1[EuBr2(phen)] chains. Seven new divalent europium complexes, [Eu(phen)4(H2O)]Br2·2MeCN, [Eu(phen)4]I2·1.7Tol, [EuBr(phen)3]2Br2·4MeCN, [EuCl2(phen)2]2·2MeCN, [EuBr2(phen)2]2, [EuI2(phen)2]2, and [EuBr2(phen)]x, are presented in this work. All species show remarkable optical properties based on a partial electron transfer from the EuII center to the Phen ligand. The photophysical characterization is further supported by electrochemistry studies in order to describe the intermediate valence of the Eu center.

Two isoforms of the essential C. elegans Argonaute CSR-1 differentially regulate sperm and oocyte fertility.

The Caenorhabditis elegans genome encodes nineteen functional Argonaute proteins that use 22G-RNAs, 26G-RNAs, miRNAs or piRNAs to regulate target transcripts. Only one Argonaute is essential under normal laboratory conditions: CSR-1. While CSR-1 has been studied widely, nearly all studies have overlooked the fact that the csr-1 locus encodes two isoforms. These isoforms differ by an additional 163 amino acids present in the N-terminus of CSR-1a. Using CRISPR-Cas9 genome editing to introduce GFP::3xFLAG into the long (CSR-1a) and short (CSR-1b) isoforms, we found that CSR-1a is expressed during spermatogenesis and in several somatic tissues, including the intestine. CSR-1b is expressed constitutively in the germline. small RNA sequencing of CSR-1 complexes shows that they interact with partly overlapping sets of 22G-RNAs. Phenotypic analyses reveal that the essential functions of csr-1 described in the literature coincide with CSR-1b, while CSR-1a plays tissue specific functions. During spermatogenesis, CSR-1a integrates into an sRNA regulatory network including ALG-3, ALG-4 and WAGO-10 that is necessary for fertility at 25°C. In the intestine, CSR-1a silences immunity and pathogen-responsive genes, and its loss results in improved survival from the pathogen Pseudomonas aeruginosa. Our findings functionally distinguish the CSR-1 isoforms and highlight the importance of studying each AGO isoform independently.

Superconductivity, correlated insulators, and Wess-Zumino-Witten terms in twisted bilayer graphene.

Recent experiments on twisted bilayer graphene have shown a high-temperature parent state with massless Dirac fermions and broken electronic flavor symmetry; superconductivity and correlated insulators emerge from this parent state at lower temperatures. We propose that the superconducting and correlated insulating orders are connected by Wess-Zumino-Witten terms, so that defects of one order contain quanta of another order and skyrmion fluctuations of the correlated insulator are a "mechanism" for superconductivity. We present a comprehensive listing of plausible low-temperature orders and the parent flavor symmetry-breaking orders. The previously characterized topological nature of the band structure of twisted bilayer graphene plays an important role in this analysis.

LPS targets host guanylate-binding proteins to the bacterial outer membrane for non-canonical inflammasome activation.

Pathogenic and commensal Gram-negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase-11 non-canonical inflammasome. Here, we show that OMV-induced inflammasome activation requires TLR4-TRIF signaling, the production of type I interferons, and the action of guanylate-binding proteins (GBPs), both in macrophages and in vivo Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram-negative bacterial outer membranes is LPS itself. Our findings provide new insights into the mechanism by which GBPs target foreign surfaces and reveal a novel function for GBPs in controlling the intracellular detection of LPS derived from extracellular bacteria in the form of OMVs, thus extending their function as a hub between cell-autonomous immunity and innate immunity.

The Unprecedented [S4 N2 O10 ]2- Anion in the Molecular Gold Complexes [Au2 Br2 (S4 N2 O10 )2 ] and [Au2 Cl2 (S4 N2 O10 )2 ](S2 O5 Cl2 ).

The reaction of hexachlorophosphazene, P3 N3 Cl6 , with SO3 and the gold halides AuCl3 and AuBr3 , respectively, leads to the new cyclic anionic tetramer, [S4 N2 O10 ]2- , which is coordinated to Au3+ in the dimeric complexes [Au2 X2 (S4 N2 O10 )2 ] (X=Cl, Br). The [S4 N2 O10 ]2- anion can be seen as the condensation product of two sulfate anions, [SO4 ]2- , and two amidosulfate anions, [NH2 SO3 ]- .

Selenous Acid in an Aromatic Framework: Insights Into a Temperature-Sensitive Internal Redox System from the Solid State.

We report on a new compound composed of a phenanthroline network in which emerging channels are alternately occupied by selenous acid (H2SeO3) and dioxane molecules. The material undergoes a variety of structural changes due to both its redox activity as well as its thermal decomposition. We investigate an internal redox system of the incorporated selenous acid and the aldehyde groups of the phenanthroline framework. The reduction process of the selenium species was further elucidated by cyclic voltammetry, while the oxidation process was also monitored by 1H NMR spectra. The thermal behavior reveals that the material can undergo a reversible, topotactic transition due to dioxane and water (de)intercalation.

Quantifying the barrier for the movement of cyclobis(paraquat-p-phenylene) over the dication of monopyrrolotetrathiafulvalene.

A bistable [2]pseudorotaxane 1⊂CBPQT·4PF6 and a bistable [2]rotaxane 2·4PF6 have been synthesised to measure the height of an electrostatic barrier produced by double molecular oxidation (0 to +2). Both systems have monopyrrolotetrathiafulvalene (MPTTF) and oxyphenylene (OP) as stations for cyclobis(paraquat-p-phenylene) (CBPQT4+). They have a large stopper at one end while the second stopper in 24+ is composed of a thioethyl (SEt) group and a thiodiethyleneglycol (TDEG) substituent, whereas in 1⊂CBPQT4+, the SEt group has been replaced with a less bulky thiomethyl (SMe) group. This seemingly small difference in the substituents on the MPTTF unit leads to profound changes when comparing the physical properties of the two systems allowing for the first measurement of the deslipping of the CBPQT4+ ring over an MPTTF2+ unit in the [2]pseudorotaxane. Cyclic voltammetry and 1H NMR spectroscopy were used to investigate the switching mechanism for 1⊂CBPQT·MPTTF4+ and 2·MPTTF4+, and it was found that CBPQT4+ moves first to the OP station producing 1⊂CBPQT·OP6+ and 2·OP6+, respectively, upon oxidation of the MPTTF unit. The kinetics of the complexation/decomplexation process occurring in 1⊂CBPQT·MPTTF4+ and in 1⊂CBPQT·OP6+ were studied, allowing the free energy of the transition state when CBPQT4+ moves across a neutral MPTTF unit (17.0 kcal mol-1) or a di-oxidised MPTTF2+ unit (24.0 kcal mol-1) to be determined. These results demonstrate that oxidation of the MPTTF unit to MPTTF2+ increases the energy barrier that the CBPQT4+ ring must overcome for decomplexation to occur by 7.0 kcal mol-1.

Tetramodal therapy with transurethral resection followed by chemoradiation in combination with hyperthermia for muscle-invasive bladder cancer: early results of a multicenter phase IIB study.

BACKGROUND: Transurethral resection of bladder tumor (TUR-BT) followed by chemoradiation (CRT) is a valid treatment option for patients with muscle-invasive bladder cancer (MIBC). This study aimed to investigate the efficacy of a tetramodal approach with additional regional hyperthermia (RHT). METHODS: Patients with stages T2-4 MIBC were recruited at two institutions. Treatment consisted of TUR-BT followed by radiotherapy at doses of 57-58.2 Gy with concurrent weekly platinum-based chemotherapy and weekly deep RHT (41-43 °C, 60 min) within two hours of radiotherapy. The primary endpoint was a complete response six weeks after the end of treatment. Further endpoints were cystectomy-free rate, progression-free survival (PFS), local recurrence-free survival (LRFS), overall survival (OS) and toxicity. Quality of life (QoL) was assessed at follow-up using the EORTC-QLQ-C30 and QLQ-BM30 questionnaires. Due to slow accrual, an interim analysis was performed after the first stage of the two-stage design. RESULTS: Altogether 27 patients were included in the first stage, of these 21 patients with a median age of 73 years were assessable. The complete response rate of evaluable patients six weeks after therapy was 93%. The 2-year cystectomy-free rate, PFS, LRFS and OS rates were 95%, 76%, 81% and 86%, respectively. Tetramodal treatment was well tolerated with acute and late G3-4 toxicities of 10% and 13%, respectively, and a tendency to improve symptom-related quality of life (QoL) one year after therapy. CONCLUSION: Tetramodal therapy of T2-T4 MIBC is promising with excellent local response, moderate toxicity and good QoL. This study deserves continuation into the second stage.